2, N6 -disubstituted adenosines, tri-O-ester derivatives and their pharmaceutical compositions to treat ischemias

ABSTRACT

A compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR1## wherein X is halogen, trifluoromethyl, cyano, C 1-6  -alkoxy, C 1-6  -alkylthio, C 1-6  -alkylamino or C 1-6  -dialkylamino; 
     R 1  and R 4  are H or straight or branched C 1-6  -alkyl or trifluoromethyl or R 1  and R 4  together form a cycloalkyl ring; 
     Y is O, S, SO 2 , NH or N-alkyl; 
     R 5  is selected from optionally substituted heterocycles. 
     R 6  and R 7  are hydrogen, benzoyl or C 1-6  -alkanoyl. 
     The compounds have been found useful for treating central nervous system and cardiovascular ailments.

The present invention relates to therapeutically active N-substitutedadenosine derivatives which are substituted at the purine 2-position andpharmaceutically acceptable addition salts thereof, processes for theirpreparation as well as methods for alleviation of diseases treatable viaadenosine receptors, to compounds for use in such a method and topharmaceutical compositions containing the said compounds.

BACKGROUND OF THE INVENTION

Adenosine is a naturally occurring purine nucleoside, from which isderived a range of agonists at adenosine receptors having considerablepotential in the treatment of human disease (Life Sciences, 1991, 49,1435-1453; Journal of Medicinal Chemistry, 1992, 35,407-422; AnnualReports in Medicinal Chemistry, 1993, 28, 295-304).

Adenosine has been shown to have a number of significant effects on themammalian central nervous system (CNS) (Annual Reports in MedicinalChemistry, 1988, 23, 39-48; Adenosine in the Nervous System, T. W.Stone, Ed., Academic Press Ltd., London 1991) especially underconditions of neuronal stress where the compound appears to act as anendogenous neuroprotectant (Progress in Neurobiology, 1988, 31, 85-108,Trends in Pharmacological Sciences, 1992, 11,439-445). For example, theconcentration of adenosine has been demonstrated to rise greatly incertain brain regions following epileptic seizures or conditions ofneuronal ischaemia/anoxia (Brain Research, 1990, 516, 248-256).

It has been established for some years now that centrally actingadenosine receptor agonists or compounds which increase extracellularadenosine levels can exhibit what is termed neuromodulator activity(Trends in Neurosciences, 1984, 164-168). Such substances influence therelease of neurotransmitters in regions of the central nervous system(Annual Review of Neuroscience, 1985, 8, 103-124; Trends inNeurosciences, 1984, 164-168), with particular inhibitory effects on therelease of the excitatory amino acid glutamic acid (glutamate) in theCNS (Nature, 1985, 316, 148-150) especially under ischaemic conditions(Journal of Neurochemistry, 1992, 58, 1683-1690).

There are therefore several CNS ailments for which this adenosinereceptor mediated neuromodulator activity could be of clear therapeuticbenefit. Examples of these would include the treatment of convulsivedisorders (European Journal of Pharmacology, 1991, 195, 261-265; Journalof Pharmacology and Experimental Therapeutics, 1982, 220, 70-76;European Journal of Pharmacology, 1993, 242, 221-228), prevention ofneurodegeneration under conditions of brain anoxia/ischaemia(Neuroscience Letters, 1987, 83, 287-293; Stroke, 1988, 19, 1133-1139;Neuroscience, 1989, 30, 451-462; Pharmacology of Cerebral Ischaemia1990, (Kriegelstein, J. and Oberpichler, H., Eds., WissenschaftlicheVerlagsgesellschaft mbH: Stuttgart, 1990, pp 439-448; Trends inPharmacological Sciences 1992, 11,439-445) or the use of a purinergicagent in the treatment of pain (European Journal of Pharmacology, 1989,162, 365-369; Neuroscience Letters, 1991, 121, 267-270).

Adenosine receptors represent a subclass (P₁) of the group of purinenucleotide and nucleoside receptors known as purinoreceptors. Thissubclass has been further classified into two distinct receptor typeswhich have become known as A₁ and A₂. Extensive research has beencarried out in a quest to identify selective ligands at these sites.Selective ligands exist for A₁ and A₂ adenosine receptors and thestructure-activity relationships of the various reference ligands havebeen reviewed (Biochemical Pharmacology, 1986, 35, 2467-2481;Comprehensive Medicinal Chemistry, Volume 3, (Hansch, C., Sammes, P. G.and Taylor, J. B., Eds., Pergamon Press PLC: 1990, pp 601-642). Amongthe known adenosine receptor agonists most selective for the A₁ receptorover the A₂ receptor are the examples where the adenine nucleus issubstituted with a cycloalkyl group on the amino function, for exampleN-cyclopentyladenosine (CPA) and N-cyclohexyladenosine (CHA) (Journal ofMedicinal Chemistry, 1985, 28, 1383-1384) or2-chloro-N-cyclopentyladenosine (CCPA) (Naunyn-Schmiedeberg's Arch.Pharmacol. 1988, 337, 687-689).

Various examples of N-heteroarylalkyl substituted A₁ selective adenosineanalogues have been reported in the literature. It should be noted thatsome of these are named as N-6 or N⁶ -substituted adenosine derivatives,but this is equivalent to the American Chemical Society suggestednomenclature where compounds substituted on adenosine's 6-amino positionare referred to as N-substituted adenosine derivatives.

There is evidence for further subdivision of adenosine receptors intothe subtypes A_(2a), A_(2b) (of high and low affinity), A₃ and A₄. Thelatest status of these subtypes has been reviewed (Journal of BiologicalChemistry, 1992, 267, 6451-6454; Drug Development Research, 1993, 28,207-213; Trends in Pharmacological Sciences 1993, 290-291). The A₃receptor (Proceedings of the National Academy of Sciences of the USA,1992, 89, 7432-7436) appears to be responsible for some of thecardiovascular effects of reference ligands (British Journal ofPharmacology, 1993, 109, 3-5).

The synthesis and pharmacological properties of N-thienylalkyl andN-pyridylalkyl adenosine derivatives has been published in thescientific literature (e.g. Nucleosides and Nucleotides, 1992, 11,1077-1088; Nucleosides and Nucleotides, 1991, 10, 1563-1572; CanadianJournal of Pharmacology, 1986, 333, 313-322). Furthermore, 2-substitutedN-piperidinyladenosine derivatives have been described recently(Bioorganic and Medicinal Chemistry Letters, 1993, 3, 2661-2666).

Certain N-imidazolylalkyl and N-indolylalkyl adenosine derivatives havealso been described (Life Sciences, 1987, 41, 2295-3202; Justus LiebigsAnnalen der Chemie 1976, 4, 745-761; Chemical & Pharmaceutical Bulletin,1974, 22, 1410-13, Biochemical Pharmacology, 1974, 23, 2883-2889).

Various studies of the 6-amino subregion of adenosines which includeN-heteroarylalkyl substituents have been published (Journal of MedicinalChemistry 1986, 29, 989-996; Naunyn-Schmiedeberg's Archives ofPharmacology, 1986, 333, 313-322; Biochemical Pharmacology, 1986, 35,2467-2481).

Examples of modified adenosine derivatives containing a range ofN-heteroarylalkyl substituents have been claimed in several patents andpatent applications. For example EP 0 232 813 A2 includesN-heteroarylcycloalkylmethyl adenosines which are apparently useful asanalgesics, antipsychotics, sedatives, antihypertensives andantianginals.

U.S. Pat. No. 4,600,707 discloses N-benzothienyl adenosines and thecorresponding N-oxide and Sodioxides as antipsychotics.

In WO 8504882 N-heteroarylethyl adenosines are claimed as cardiacvasodilators. Some similar analogues containing N-heteroarylalkyladenosine compounds are included in Ger. Offen. DE 2147314, Ger. Offen.DE 2139107, EP 0 423 776 A2, EP 0 423 777 A2, U.S. Pat. No. 4,340,730and U.S. Pat. No. 1,164,580 without any mention being made of theirpotential pharmacological effects on the CNS.

PCT-publication WO 9205177 and U.S. Pat. No. 3,901,876 disclosesN-substituted adenosine derivatives with hypotensive properties, none ofthem being further substituted at the purine 2-position.

Utility of adenosine receptor agonists as cerebral neuroprotectants isclaimed in the following patents and patent publications: WO 90/05526,EP 0490818A1, U.S. Pat. No. 5,187,162, EP 526866A1, U.S. Pat. No.5,219,839, WO 93/08206, WO 93/23417 and WO 93/23418.

The present invention relates to new adenosine analogues having potentbinding in vitro to the adenosine A₁ receptor and at the same timeshowing selectivity for A₁ receptor binding in vitro over that of the A₂receptor subtype (for method description, see European Journal ofPharmacology, 1993, 242, 221-228). In addition, the compounds containedin this invention have a relatively high lipophilicity, especially whencompared to adenosine analogues which are not substituted on the 6-aminogroup or at the purine 2-position. This latter property makes thesecompounds suitable for passage across the blood brain barrier, andsupports the suggestion that the compounds may be candidate drugs forthe CNS and other ailments mentioned within this invention.

The possibility that some of the compounds may be substrates fornucleoside-specific active transport systems across the blood brainbarrier is, however, not excluded. These useful properties support thesuggestion that the compounds may be candidate drugs for the CNSailments mentioned above in humans, There are however instances where ithas been demonstrated that co-administration of a peripherally activeadenosine receptor antagonist can lower the expected dose related sideeffects on the cardiovascular system when an adenosine agonist is usedas a neuroprotectant in animal models (Journal of MolecularNeuroscience, 1990, 2, 53-59). This method of lowering potentialside-effects is also applicable during the therapeutic use of theadenosine receptor agonists covered by the present invention.

The invention also covers the potential prodrugs of the adenosinederivatives described above. Adenosine sugar moiety esters which canfind utility as prodrugs are exemplified in this patent.

The compounds of the invention are purine derivatives of formula (I), ora pharmaceutically acceptable salt thereof: ##STR2## wherein X ishalogen, amino, trifluoromethyl, C₁₋₆ -alkyl, C₁₋₆ -alkoxy, C₁₋₆-alkylthio, cyano, C₁₋₆ -alkylamino or di-C₁₋₆ -alkylamino;

R¹ is H or straight or branched C₁₋₆ -alkyl or trifluoromethyl;

R⁴ is H or straight or branched C₁₋₆ -alkyl; or

R¹ and R⁴ together form a cyclobutyl, cyclopentyl or cyclohexyl ring;

Y is O, S, SO₂, N--H or N-alkyl;

R⁵ is a group of formula (XI) or (XII): ##STR3## wherein A is --NH--,--O-- or --S--;

B is --CH-- or --N--;

C is --CH-- or --N--;

which may be optionally substituted with R⁸ which is H, phenyl, C₁₋₆-alkyl, tri-fluoromethyl, amino, hydroxy, C₁₋₆ -alkoxy, cyano orhalogen;

R⁶ is hydrogen, benzoyl or C₁₋₆ -alkanoyl and

R⁷ is hydrogen, benzoyl or C₁₋₆ -alkanoyl.

In certain examples, the group ##STR4## can contain one or moreasymmetric carbon atoms in addition to those asymmetric centres alreadypresent in the ribose moiety of these adenosine agonists. The inventionincludes all resulting diastereoisomers and mixtures thereof.

The compounds according to the invention includes various salts whichcan be considered physiologically acceptable. These include additionsalts derived from inorganic or organic acids, for example, acetates,fumarates, glutarates, glutaconates, hydrochlorides, lactates, maleates,methanesulphonates, phosphates, salicylates, succinates, sulphates,sulphamates, tartrates and para-toluenesulphonates. In some cases,solvates of either the free nucleosides or the acid addition salts canbe isolated and these solvates may, for example, be hydrates oralcoholates.

Compounds according to the invention are for instance:

[1S,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine,

[1R,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine,

[1S,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine,

[1R,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine,

[1S,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine,

[1R,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine,

[1S,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine,

[1R,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine,

N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-methoxyadenosine,

N-[(R)-1 -(2-Benzothiazolyl)oxy-2-propyl]-2-chloroadenosine or

2-Chloro-N-[(R)-1-(6-hydroxy-2-benzothiazolyl)thio-2-propyl]adenosine.

Compounds of formula (I), which act as adenosine receptor agonists, areexpected from observations in animal models to be useful in thetreatment of central nervous system conditions such as anxiety, neuronalischaemia/anoxia, convulsive disorders (f. inst. epilepsy) andneuro-degeneration (including Parkinson's disease) in humans. Thisincludes treating disorders where the blood flow to regions of the brainis interrupted, for example during traumatic head injury, cardiac arrestand stroke.

Further, the compounds of formula (I) are expected to be useful asanalgesic agents, in lowering plasma free fatty acid levels or ascardiovascular agents, e.g. for the treatment of myocardial ischaemia.

The invention also relates to methods of preparing the above mentionedcompounds. These methods comprise:

Method A

A compound of formula (I) may be prepared by reacting a substance offormula (11), wherein L represents a leaving group such as a halogenatom (e.g. a chlorine or bromine atom) or a trimethylsilyloxy group, R²and R³ are the same or different and represent hydrogen or a protectinggroup such as benzoyl-, p-toluoyl-, C₁₋₆ -alkanoyl- (e.g. acetyl-), a2,3-O-(1-methyl)- ethylidene group or a substituted silyl group (e.g. atrimethylsilyl or t-butyldimethylsilyl group) (for descriptions seeNucleic Acid Chemistry, Townsend L. B. and Tipson, R. S., eds., JohnWiley and Sons Inc., 1986, 3. and earlier volumes) with an aminederivative of general formula (111), synthesised according to methodsknown in the art (see for example WO 93/08206 and WO 93/23418) ##STR5##giving the compound of formula (IV) as the reaction product. In caseswhere R² and R³ are not hydrogen an additional step will be required toremove protecting groups from a compound of formula (IV); in cases wherethe groups R² and R³ are for example C₁₋₆ -alkanoyl- or benzoyl-,suitable conditions for deprotection include methanolic ammonia, analkali metal carbonate in methanol, an alkali metal alkoxide in thecorresponding alcohol. Where the protecting groups are for examplealkylsilicon or arylsilicon derivatives, suitable deprotection methodsinclude for example treatment with tetraalkylammonium fluorides oraqueous hydrolysis in the presence of acid or base.

Method B

A compound of formula (I) wherein X represents --NH--R⁹, S--R⁹ or--O--R⁹, where R⁹ is C₁₋₆ -alkyl may be prepared by reacting a substanceof general formula (V) ##STR6## (where L is a leaving group as definedin method (A)) with a nucleophile, for example C₁₋₆ -alkylamino(optionally in the presence of a suitable base) or with the anion (C₁₋₆-alkoxide or C₁₋₆ -thioalkoxide) to afford (IV). In cases where R² andR³ are hydrogen, a compound of formula (I) can be obtained directly.However, in cases where R² and R³ are not hydrogen an additional stepwill be involved to remove protecting groups such as C₁₋₆ -alkanoyl- orbenzoyl- from a compound of formula (IV); examples of conditions forremoval of protecting groups are given in process (A). In some reactionsinvolving nucleophilic substitution of a compound of formula (V) withthe anion (C₁₋₆ -alkoxide or C₁₋₆ -thioalkoxide), where R² and R³ arefor example C₁₋₆ -alkanoyl- or benzoyl- partial or full deprotection maytake place. In cases where only partial deprotection has taken place,deprotection can be completed under conditions exemplified in method(A).

Method C

A compound of formula (I) may be prepared by reacting a substance of thegeneral formula (VI) (where B represents ##STR7## or L as definedpreviously) with a diazotising agent (such as, for example,3-methylbutyl nitrite) to form a diazoointermediate which can be reactedfurther with a variety of substrates (for example chloroform,tetrachloroethane, trimethylsilylchloride, bromoform or fluoroboricacid) as exemplified below in order to introduce the group -X into acompound of formula (VII). ##STR8##

In the case where B represents a leaving group L, a further displacementreaction with for example a compound of formula (111) will be requiredin order to obtain a compound of formula (IV). In cases where the groupsR² and R³ are not hydrogen, or not all hydrogen, another step will berequired to remove protecting groups from a compound of formula (IV);conditions for removing protecting groups are described in method A.

Compounds of formula (I) in which R⁶ and R⁷ are C₁₋₆ -alkanoyl- orbenzoyl-, may be prepared according to methods A-C as compounds offormula (IV) and (VII) in which R² and R³ are represented by C₁₋₆-alkanoyl- or benzoyl-. In cases where R² and R³ are different from R⁶and R⁷, R² and R³ can be replaced with hydrogen, C₁₋₆ -alkanoyl- orbenzoyl- according to methods known in the art.

Methods for assessing adenosine receptor binding in vitro have beenreviewed [Adenosine Receptors, (Cooper, D. M. F. and Londos, C., eds.)Alan R. Liss, Inc., New York, 1988, 43-62].

Evaluation of these compounds in established animal models has indicatedthat the compounds according to the invention possess desirable centralnervous system properties. For example, they act as anticonvulsantagents, are effective in animal paradigms of pain, and showcerebroprotective effects in laboratory test animals subjected tosimulated cerebral ischaemia. In addition, the compounds may haveefficacy as neuroprotective agents in cases of cerebral oedema andtraumatic head injury, and as protectants in myocardial ischaemia.

Evaluation of in vitro Binding to Adenosine A₁ and A₂ Receptors

The affinity of the novel compounds described in this invention for theadenosine A₁ receptor was determined essentially as described in theliterature using [³ H]-(R)-PIA [N-(R)-(1-phenyl-2-propyl)adenosine] as aradioligand (Naunyn-Schmiedeberg's Archives of Pharmacology, 1980, 313,179-187). Affinity for the A₂ receptor was measured using theradioligand [³ H]-CGS 21680 (European Journal of Pharmacology, 1989,168, 243-246), and the values for representative compounds (singledeterminations only) are given in the table below. In vitro receptorbinding values obtained for the reference standards CPA and (R)-PIA areincluded for comparison. The methods used are described fully inEuropean Journal of Pharmacology, 1993, 242, 221-228.

DMCM INDUCED SEIZURES IN MICE, I.P.30 min

DMCM (methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate) is aninverse agonist at the benzodiazepine receptor, presumably producingseizures by decreasing the potency of inhibition of the GABAreceptor/benzodiazepine receptor/chloride ionophore complex.

METHODS

18 mg/kg of DMCM dissolved in 0.02 N HCl (1 mg/ml)is administered i.p.in a volume of 300/71 to male NMRI mice weighing 20±2 g. This inducestwo different responses: a) some animals manifest a brief loss ofrighting reflexes or take up an upright position in which they have amild short clonus of the upper extremities, b) other animals manifestintense clonic and tonic convulsions of all extremities often followedby death. DMCM is administered 30 min after an intraperitoneal injectionof a test compound. The latency time for the presence of intense clonicand tonic convulsions and death is noted until 15 min afteradministration of DMCM. At least 5 doses of each test compound aretested with 8 mice per dose. This method is described in more detail inEuropean Journal of Pharmacology, 1993, 242, 221-228.

Test results obtained by testing compounds of the invention arepresented in table I.

                  TABLE I                                                         ______________________________________                                                     A.sub.1    A.sub.2                                               Adenosine    receptor   receptor                                              agonist tested                                                                             binding    binding    Ratio                                      (Example No.)                                                                              (K.sub.i, nM)                                                                            (K.sub.i, nM)                                                                            A.sub.2 /A.sub.1                           ______________________________________                                        13           3.4        2570       756                                        23           4.5        170         38                                        15           7          950        136                                         3           9          990        110                                        22           10         1000       100                                        27           14         4970       355                                        CPA          1.2        192        160                                        (R)-PIA      1.9        116         61                                        ______________________________________                                    

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, and if desired in the form of a pharmaceuticallyacceptable acid addition salt thereof, may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets of filled capsules, orliquids, such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral use (including subcutaneous administration and infusion).Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principles, and such unit dosageforms may contain any suitable effective amount of the adenosinereceptor agonist commensurate with the intended daily dosage range to beemployed. Tablets containing ten (10) milligrams of active ingredientor, more broadly, ten (1 0) to hundred (100) milligrams, per tablet, areaccordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation ofpharmaceutical preparation, e.g. for oral and parenteral administrationto mammals including humans, in accordance with conventional methods ofgalenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral or enteralapplication which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Ampoules are convenient unit dosage forms.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like, the carrier preferably being lactose and/or cornstarch and/or potato starch, are particularly suitable for oralapplication. A syrup, elixir or the like can be used in cases where asweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit formcomprising 0.05-100 mg in a pharmaceutically acceptable carrier per unitdosage.

The dosage of the compounds according to this invention is 0.1-300mg/day, preferably 10-100 mg/day, when administered to patients, e.g.humans, as a drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________                                        Active compound    5.0     mg                                                 Lactosum           67.0    mg Ph. Eur.                                        Avicel ™        31.4    mg                                                 Amberlite ™ IRP 88                                                                            1.0     mg                                                 Magnesii stearas   0.25    mg Ph. Eur.                                        ______________________________________                                    

As a result of their activity against pain or convulsive disorders andprevention of neurodegeneration under conditions of anoxia/ischaemia thecompounds of the invention are extremely useful in the treatment ofrelated symptoms in mammals, when administered in an amount effectivefor agonist activity of compounds of the invention. The compounds of theinvention may accordingly be administered to a subject, e.g., a livinganimal body, including a human, in need of adenosine receptor agonist,and if desired in the form of a pharmaceutically acceptable acidaddition salt thereof (such as the hydrobromide, hydrochloride, orsulphate, in any event prepared in the usual or conventional manner,e.g., evaporation to dryness of the free base in solution together withthe acid), ordinarily concurrently, simultaneously, or together with apharmaceutically acceptable carrier or diluent, especially andpreferably in the form of a pharmaceutical composition thereof, whetherby oral, rectal, or parenteral (including subcutaneous) route, in aneffective amount of adenosine receptor agonist, and in any event anamount which is effective for the treatment of anoxia, traumatic injury,ischaemia, migraine or other pain symptoms, epilepsy, orneurodegenerative diseases owing to their adenosine receptor agonistactivity. Suitable dosage ranges are 1-200 milligrams daily, 10-100milligrams daily, and especially 5-25 milligrams daily, depending asusual upon the exact mode of administration, form in which administered,the indication toward which the administration is directed, the subjectinvolved and the body weight of the subject involved, and the preferenceand experience of the physician or veterinarian in charge.

The preparation of compounds of formula (I) is further illustrated inthe following examples.

Hereinafter, TLC is thin layer chromatography, THF is tetrahydrofuran,TFA is trifluoracetic acid and m.p. is melting point. Where meltingpoints are given, these are uncorrected. The structures of the compoundsare confirmed by assignment of 400 MHz NMR spectra (from whichrepresentative peaks are quoted) and by microanalysis where appropriate.Compounds used as starting materials are either known compounds orcompounds which can be prepared by methods known per se. Columnchromatography was carried out using the technique described by Still,W. C. et al., Journal of Organic Chemistry, 1978, 43, 2923 on Mercksilica gel 60 (Art 9385). HPLC was carried out on a Waters model 510chromatograph interfaced via a system module to a Waters 490multi-wavelength detector to a reversed phase C₁₈ column (250×4 mm, 5μm, 100Å; eluent flow rate 1 ml/min). Retention times are given inminutes.

EXAMPLE 1 2-Chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl]adenosine

The title compound was prepared according to general method A.

2',3',5'-Tri-O-benzoyl-2-chloro-N-[(R)-1-(thiazolyl)thio-2-propyl]adenosine

To a suspension of 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (4.0g, 23 mmol), 2-mercaptothiazole (2.9 g, 25 mmol) and triphenylphosphine(7.3 g, 28 mmol) in dry toluene (50 ml) under nitrogen, a solution ofdiisopropylazocarboxylate (4.9 g, 28 mmol) in dry toluene (30 ml) wasadded dropwise. The reaction mixture was stirred for 40 h at 20° C. andfiltered. The filtrate was evaporated to an oil prior to purification by"flash" chromatography. Elution with a mixture of heptane and ethylacetate (3:2) provided2-[2-(R)-tert-butyloxycarbonylamino-1-propylthio]thiazole (3.0 g, 48%)as an oil, TLC R_(f) 0.33 [heptane/ethyl acetate (3:2)].

2-[2-(R)-tert-butyloxycarbonylamino-1-propylthio]thiazole (3.0 g, 11mmol) was dissolved in ethyl acetate (30 ml) and a 6N solution ofhydrochloric acid in dry ethyl acetate (15 ml) was added. After 20 h atroom temperature the reaction mixture was filtered to provide crude2-[(R)-2-aminopropyl-1-propylthio]thiazole as a hygroscopic, apparentdihydrochloride salt (2.3 g).

To a solution of9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g,2.4 mmol) in dry dioxan (50 ml), the above2-[(R)-2-aminopropyl-1-propylthio]thiazole dihydrochloride (1.5 g, 7.1mmol) and triethylamine (0.78 g, 7.7 mmol) were introduced at 20° C.After stirring at 50° C. for 40 h the reaction mixture was concentratedto a yellow oil, which was purified by flash chromatography eluting witha mixture of heptane and ethyl acetate (1:1), to afford the title2',3',5'-tri-O-benzoyl-2-chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl]adenosine(1.2 g, 63%) as a foam, TLC R_(f) 0.19 [SiO₂ ; heptane/ethyl acetate(1:1)].

2-Chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl)]adenosine

2',3',5'-Tri-O-benzoyl-2-chloro-N-[(R)-1-(2othiazolyl)thio-2-propyl]adenosine(1.2 g, 1.5 mmol) was dissolved in methanolic ammonia (25 ml)(previously saturated at -10° C.) and stirred at 20° C. for 40 h. Thereaction mixture was concentrated to an oil at reduced pressure andpurified by flash chromatography eluting with a mixture ofdichloromethane, ethanol and ammonia (90: 10:1), to provide the title2-chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl)]adenosine (0.32 g, 46%) asa foam, ¹ H NMR (DMSO-d₆) δ 1.31 (3H, d, CHCH₃), 3.95 (1H, q, H-4'),4.12 (1 H, q, H-3'), 4.51 (1 H, q, H-2'), 5.07 (1 H, t, 5'-OH), 5.22,5.50 (2H, 2d, 2'-and 3'-OH), 5.82 (1H, d, H-1'), 7.63 (1H, d, Ar-H),7.72 (1H, d, Ar-H), 8.41 (1H, s, H-8), 8.48 (1H, d, N--H).

C₁₆ H₁₉ CIN₆ O₄ S₂, H₂ O requires C, 41.1; H, 4.3; N, 18.0. Found: C,41.2; H, 4.3; N, 17.4%.

EXAMPLE 22-Chloro-N-[(R)-1-(1-methyl-2-imidazolyl)thio-2-propyl]adenosine

The title compound was prepared according to method A as described abovein Example 1 by reacting (R)-1-(1-methyl-2-imidazolyl)thio-2-propylaminehydrochloride [prepared using the same method as described in Example 1from 2-mercapto-1-methylimidazole (3.31 g, 29 mmol) and2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (5.08 g, 29 mmol)followed by acidic hydrolysis] (2.30 g, 11.1 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.46 g,5.5 mmol), followed by debenzoylation of the purified product usingmethanolic ammonia. This provided the title2-chloro-N[(R)-1-(1-methyl-2-imidazolyl)-thio-2-propyl]adenosine (1.1 g,43%) as a foam after column chromatography. ¹ H NMR (DMSO-d₆) δ 1.28(3H, d, --CHCH₃), 3.53-3.60 (1 H, m, H-5'_(a)), 3.63-3.70 (1H, m,H-5'_(b)), 3.95 (1H, q, H- 4'), 4.13 (1H, q, H-3'), 4.51 (1 H, q, H-2'),5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.82 (1H, d,H-1'), 6.92 (1H, s, Ar-H) 7.20 (1H, s, Ar-H), 8.40 (1H, s, H-8), 8.55(1H, s, N--H). HPLC retention time 19.3 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₁₇ H₂₂ CIN₇ O₄ S. 1.0 H₂ O requires C, 43.1; H, 5.1; N, 20.7. Found: C,43.4; H, 5.0; N, 20.7%.

EXAMPLE 3 2-Chloro-N-{(R)-1-[5-methyl-(1,3,4-thiadiazol-2-yl)]thio-2-propyl}adenosine

The title compound was prepared according to method A as described abovein Example 1 by reacting 2-[(R)-2-amino-1-propylthio]-5-methyl-[1,3,4]-thiadiazole hydrochloride [prepared by alkylation of2-mercapto-5-methyl-(1,3,4)-thiadiazole (1.32 g, 10 mmol) usingmethanesulphonic acid, 2-[(R)-N-tert-butyloxycarbonylamino]-1-propylester (3.04 g, 12 mmol) followed by acidic hydrolysis] (1.01 g, 4.47mmol) with9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.36g, 3.73 mmol), followed by debenzoylation of the purified product usingmethanolic ammonia. This provided the title2-chloro-N{(R)-1-[5-methyl(1,3,4-thiadiazol-2-yl)]thio-2-propyl}adenosine(0.94 g, 53%) as a foam after column chromatography. ¹ H NMR (DMSO-d₆) δ1.35 (3H, d, --CHCH₃), 2.67 (3H, s, --CH₃), 3.53-3.61 (2H, m, H-5'_(a)and H-5'_(b)), 3.96 (1H, q, H-4), 4.14 (1H, q, H-3'), 4.52 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H,d, H-1'), 8.33-8.46 (2H, m, H-8 and --NH). HPLC retention time 9.9 min[gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 4 N-[(R)-1-(2-Benzoxazolyl)thio-2-propyl]-2-chloroadenosine

The title compound was prepared essentially according to method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]benzoxazole hydrochloride [prepared byalkylation of 2-mercaptobenzoxazole (3.5 g, 23 mmol) usingmethanesulphonic acid, 2-[(R)-N-tert-butyloxycarbonylamino]-1-propylester (7.2 g, 30 mmol) followed by acidic hydrolysis] (1.7 g, 6 mmol)with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine(2.7 g, 6.0 mmol), followed by deacylation of the purified product usingsodium methoxide in methanol. This provided the titleN-[(R)-1-(2-benzoxazolyl)thio2-propyl]-2-chloroadenosine (0.37 g, 28%)as a foam after column chromatography. ¹ H NMR (DMSO-d₆) δ 1.38 (3H, d,--CHCH₃), 3.40-3.75 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --), 3.94(1H, q, H-4), 4.12 (1H, q, H-3'), 4.52 (1H, m, H-2'), 5.06 (1H, t,5'-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.82 (1H, d, H-1'),7.26-7.35 (2H, m, Ar-H), 7.53-7.64 (2H, m, Ar-H), 8.39 (1H, s, H-8),8.48 (1H, d, --NH).

C₂₀ H₂₁ CIN₆ O₅ S. 0.25 EtOH requires C, 48.8; H, 4.5; N, 16.6. Found:C, 48.6; H, 4.5; N, 16.5%.

EXAMPLE 5 N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-chloroadenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride [prepared by aMitsunobu reaction as described in Example 1 using2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (2.5 g, 14 mmol) and2-mercaptobenzothiazole (2.3 g, 14 mmol) followed by acidic hydrolysis](1.7 g, 5.7 mmol) with9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.8 g,4.5 mmol), followed by debenzoylation of the purified2',3',5'-tri-O-benzoyl-2-chloro-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosinein methanolic ammonia (200 ml) (previously saturated at -10° C.) toprovide the title2-chloro-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine (1.05 g,24%) (following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.38 (3H, d,--CHCH₃), 3.50-3.68 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --), 3.95(1H, d, H-4'), 4.12 (1H, d, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t,5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.34,7.45 (2H, 2t, Ar-H), 7.85, 7.98 (2H, 2d, Ar-H), 8.40 (1H, s, H-8), 8.53(1H, d, N--H). HPLC retention time 16.6 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₂₀ H₂₁ CIN₆ O₄ S₂. 0.5 EtOH requires C, 47.4; H, 4.5; N, 15.8. Found:C, 7.3; H, 4.5; N, 15.8%.

EXAMPLE 6 N-[(S)-1-(2-Benzothiazolyl)thio-2-propyl]-2-chloroadenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(S)-2-amino-1-propylthio]benzothiazole hydrochloride [prepared by aMitsunobu reaction as laid out in Example 1 using2-[(S)-N-tert-butyloxycarbonyl]amino-1-propanol (3.5 g, 20 mmol) and2-mercaptobenzothiazole (3.35 g, 20 mmol) followed by acidic hydrolysis](1.1 g, 4.2 mmol) with9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.8 g,4.5 mmol), followed by debenzoylation of the purified2',3',5'-tri-O-benzoyl-2-chloro-N-[(S)-1-(2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the title2-chloro-N-[(S)-1-(2-benzothiazolyl)thio-2propyl]adenosine (0.88 g, 49%)(following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.38 (3H, d,--CHCH₃), 3.50-3.68 (4H, m, H-5'_(a), and H-5'_(b) and --CH₂ --), 3.95(1H, d, H-4'), 4.12 (1H, d, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t,5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.34,7.45 (2H, 2t, Ar-H), 7.85, 7.98 (2H, 2d, Ar-H), 8.40 (1H, s, H-8), 8.52(1H, s, N--H). HPLC retention time 20.1 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₂₀ H₂₁ CIN₆ O₄ S₂. 1.5 H₂ O requires C, 44.8; H, 4.5; N, 15.7. Found:C, 44.9; H, 4.1; N, 15.2%.

EXAMPLE 7 N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-bromoadenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared asindicated in Example 5) (1.07 g, 3.6 mmol) with2-bromo-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-9H-purine (seeWO 93/08206; Bioorganic and Medicinal Chemistry Letters, 1993, 3,2661-2666) (1.48 g, 3.0 mmol) followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-bromo-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the titleN-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-bromoadenosine (0.20 g, 14%)as a foam (following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.38(3H, d, --CHCH₃), 3.50-3.77 (4H, m, H-5'_(a), and H-5'_(b) and --CH₂--), 3.94 (1H, d, H-4'), 4.12 (1 H, d, H-3'), 4.51 (1H, q, H-2'), 4.701H, m, --CHCH₃), 5.05 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2'- and3'-OH), 5.83 (1H, d, H-1'), 7.36, 7.46 (2H, 2t, Ar-H), 7.86, 7.99 (2H,2d, Ar-H), 8.40 (1H, s, H-8). HPLC retention time 6.74 min [gradientelution, 20-80% acetonitrile/water (containing 0.1% TFA)].

C₂₀ H₂₁ N₆ BrO₄ S₂. 0.1 H₂ O requires C, 43.3; H, 3.8; N, 15.1. Found:C, 43.7; H, 4.3; N, 14.7%.

EXAMPLE 8 N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-methyladenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared asdescribed in Example 5) (0.89 g, 3.0 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methyl-9H-purine(1.07 g, 2.5 mmol) [prepared from 2-methylinosine (Journal of OrganicChemistry, 1967, 32, 3258-3260) by standard acylation and chlorinationsteps]. Deacylation of the purified2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)thio°2-propyl]-2-methyladenosine using sodium methoxide in methanol toprovide the desiredN-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methyladenosine (0.28 g,11%) (following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.40 (3H, d,--CHCH₃), 2.30 (3H, S, --CH₃), 3.50-3.77 (4H, m, H-5'_(a) and H-5'_(b)and --CH₂ --), 3.98 (1H, d, H-4'), 4.13 (1H, d, H-3'), 4.63 (1H, q,H-2'), 4.86 (1H, br, --CHCH₃), 5.19, 5.42 (2H, 2d, 2'- and 3'-OH), 5.70(1H, t, 5'-OH), 5.85 (1H, d, H-1'), 7.36, 7.47 (2H, 2t, Ar-H), 7.80-7.96(2H, m, Ar-H), 8.0 (1H, s, N--H), 8.26 (1H, s, H-8), 8.52 (1H, s, N--H).HPLC retention time 22.4 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)]. C₂₁ H₂₄ N₆ O₄ S₂.H₂ Orequires C, 49.8; H, 4.8; N, 16.6. Found: C, 49.9; H, 5.1; N, 16.4%.

EXAMPLE 9N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methylthioadenosine

The title compound was prepared according to general method A.9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-9H-purine(Nucleic Acid Chemistry, Townsend L. B. and Tipson, R. S., eds., JohnWiley and Sons Inc., 1986, 3, 144) (4.0 g, 9.3 mmol) was dissolved inacetonitrile (100 ml). Isoamylnitrite (10.84 g, 93 mmol) was introducedfollowed by methyl disulphide (4.14 ml, 46 mmol) and the reactionmixture was heated at an oil bath temperature of 100° C. for 2 h. Theevolved gas was oxidised using a hypochlorite scrubber. The reactionmixture was cooled, evaporated and purified by flash chromatography onsilica gel. Elution initially with dichloromethane, followed bydichloromethane/methanol (100:1) provided9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methylthio-9H-purine(3.1 g, 72%) as a foam, ¹ H NMR (CDCl₃) δ 2.12, 2.14, 2.18 (9H, 3s, 2',3' and 5'-O-acetyl CH₃), 2.66 (3H, s, --SCH₃), 4.28-4.51 (3H, m,H-5'_(a), H-5'_(b) and H-4'), 5.66 (1H, t, H-3'), 6.0 (1H, t, H-2'),6.13 (1H, d, H-1'), 8.11 (1H, s, H-8).

The above9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-2-methylthio-9H-purine(0.5 g, 1.1 mmol) was reacted with2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (0.5 g, 1.5mmol) (by the procedure described in Example 5) followed by deacylationof the purified2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-methylthioadenosineusing methanolic ammonia (200 ml) (previously saturated at -10° C.) toprovide the title compoundN-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2methylthioadenosine (0.085 g,16%) as a foam (following column chromatography), ¹ H NMR (DMSO-d₆) δ1.39 (3H, d, --CHCH₃), 2.31. (3H, s, --SCH₃), 3.46-3.71 (4H, m, H-5',and H-5'_(b) and --CH₂), 3.92 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.60(1H, q, H-2'), 4.70-4.91 (1H, m, --CH), 5.05 (1H, t, 5'-OH), 5.22, 5.45(2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.31-7.53 (2H, m, Ar-H),7.84, 8.0 (2H, 2d, Ar-H), 8.10 (1H, d, N--H), 8.25 (1H, s, H-8).

EXAMPLE 10N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-(dimethylamino)adenosine

The title compound was prepared according to general method B byreaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine(1.02 g, 2.0 mmol) (Example 5)in dimethylformamide (10 ml) to providethe desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(dimethylamino)adenosine (0.12 g, 12%) as a foam (following column chromatography), ¹H NMR (DMSO-d₆) δ 1.38 (3H, d, --CHCH₃), 2.92 (6H, s, --N(CH₃)₂),3.40-3.72 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --), 3.88 (1H, q,H-4'), 4.15 (1H, q, H-3'), 4.65 (1H, q, H-2'), 4.72-4.85 (1H, m,--CH--), 4.89 (1H, t, 5'-OH), 5.14, 5.36 (2H, 2d, 2'- and 3'-OH), 5.75(1H, d, H- 1'), 7.35, 7.46 (2H, 2 t, Ar-H), 7.50 (1H, d, N--H), 7.84,7.99 (2H, 2d, Ar-H), 7.94 (1H, s, H-8). HPLC retention time 16.8 min[gradient elution, 20-80% acetonitrile/water (containing 0. 1% TFA)].

C₂₂ H₂₆ N₇ O₄ S₂. 0.5 H₂ O requires C, 50.2; H, 5.2; N, 18.6. Found: C,50.5; H, 5.7; N, 18.2%.

EXAMPLE 11N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-(ethylamino)adenosine

The title compound was prepared according to general method B byreaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-bromoadenosine(Example 7) (0.24 g, 0.35 mmol) with 70% w/w aqueous ethylamine (0.23 g)in dioxan (10ml) in a sealed vessel at 100° C. to provide the desiredN-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(ethylamino)adenosine as afoam (following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.04 (3H, brt, --NCH₂ CH₃), 1.42 (3H, d, --CHCH₃), 3.20 (3H, br m, --NCH₂ CH₃),3.55-3.80 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --), 3.95 (1H, qH-4'), 4.15 (1H, q, H-3'), 5.16, 5.41 (2H, 2d, 2'- and 3'-OH), 5.79 (1H,d, H-1'), 6.22 (1H, t, --NHCH₂ CH₃), 7.43, 7.54 (2H, 2 t, Ar-H), 7.98(1H, s, H-8). HPLC retention time 17.0 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 12 2-Amino-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]benzothiazole hydrochloride (prepared asdescribed in Example 5) (7.13 g, 24 mmol) with2-amino-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-6-chloro-9H-purine(Nucleic Acid Chemistry, Townsend L. B. and Tipson, R. S., eds., JohnWiley and Sons Inc., 1986, 3, 144) (8.56 g, 20 mmol) followed bydeacylation of a portion of the purified2',3',5'-tri-O-acetyl-2-amino-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the title2-amino-N-[(R)-1-(2-benzothiazolyl)thio2-propyl]adenosine (0.71 g, 19%)as a foam (following column chromatography) ¹ H NMR (DMSO-d₆) δ 1.34(3H, d, --CHCH₃), 3.50-3.73 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --),3.90 (1H, q, H- 4'), 4.10 (1H, d, H-3'), 4.51 (1H, q, H-2'), 5.11, 5.37(2H, 2d, 2'- and 3'-OH), 5.40 (1H, t, 5'-OH), 5.73 (1H, d, H-1'), 5.79(1H, br, --NH₂), 7.36, 7.47 (2H, 2t, Ar-H), 7.92 (1H, s, H-8), 8.0 (1H,d, N--H). HPLC retention time 13.5 min [gradient elution, 20-80%acetonitrile/water (containing 0. 1% TFA)].

EXAMPLE 13 N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-fluoroadenosine

The title compound was prepared according to general method C byreacting9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-9H-purine (seeExample 9) (0.45 g, 0.73 mmol) using the diazotisation/fluoroboric acidmethod described previously (see WO 93/08206; Bioorganic and MedicinalChemistry Letters, 1993, 3, 2661-2666) to provide2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-fluoroadenosine (0.19 g, 43%), followed by deacylation using sodiummethoxide in methanol to provide the titleN-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-fluoroadenosine (0.088 g)(following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.37 (3H, d,--CHCH₃, 3.50-3.79 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --), 3.95(1H, d, H-4'), 4.13 (1H, m, H-3'), 4.51 (1H, q, H-2'), 4.67 (1H, br,--CHCH₃), 5.07 (1H, t, 5'-OH), 5.23, 5.50 (2H, 2d, 2'- and 3'-OH), 5.79(1H, d, H-1'), 7.37, 7.48 (2H, 2t, Ar-H), 7.85, 7.79 (2H, 2d, Ar-H),8.36 (1H, s, H-8), 8.58 (1H, d, N--H). HPLC retention time 18.9 min[gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].

C₂₀ H₂₁ FN₆ O₄ S₂. 1.25 H₂ O requires C, 46.6; H, 4.1; N, 16.3. Found:C, 46.5; H, 4.5; N, 16.3%.

EXAMPLE 14 N-[(S)-2-(2-Benzothiazolyl)thio-1-propyl]-2-chloroadenosine

(S)-(2-Benzothiazolyl)thio-1-propylamine (1.5 g, 5.0 mmol) (prepared bythe method described in Example 1 from (S)-2-hydroxypropylamine) wasreacted with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.49 g,2.4 mmol) in dioxan (20 ml) in the presence of triethylamine (2.77 ml,20 mmol) to provide2',3',5'-tri-O-acetyl-N-[(S)-2-(2-benzothiazolyl)thio-1-propyl]-2-chloroadenosine,which was deacylated using methanolic ammonia (previously saturated at-10° C.) to provide the titleN-[(S)-2-(2-benzothiazolyl)thio-1-propyl]-2-chloroadenosine (0.78 g,47%) as a foam (following column chromatography), ¹ H NMR (DMSO-d₆) δ1.52 (3H, d, --CH₃), 3.56 (1H, ABX, H-5'_(a)), 3.68 (1H, m, H-5'_(b)),3.73-3.91 (1H, m, --C--H), 3.84-3.92 (1H, m, --C--H), 3.96 (1 H, q,H-4'), 4.15 (1H, m, H-3'), 4.53 (1H, dd, H-2'), 5.08 (1H, t, 5'-OH),5.23, 5.50 (3H, 3 br, 2' and 3'-OH), 5.84 (1H, d, H-1'), 7.36, 7.47 (2H,2, Ar-H), 7.83, 7.99 (2H, 2d, Ar-H), 8.40 (1H, s, H-8), 8.72 (1H, t,N--H). HPLC retention time 17.8 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₂₀ H₂₁ CIN₆ O₄ S₂. 0.5 H₂ O. 0.1 EtOAC requires C, 46.5; H, 4.4; N,16.0. Found: C, 46.6; H, 4.4; N, 15.8%.

EXAMPLE 15 N-[(R)-1-(2-Benzothiazolyl)thio-2-butyl]-2-chloroadenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-butylthio]benzothiazole hydrochloride (1.16 g, 4.2mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.57 g,3.5 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol. This provided the titleN-[(R)-1-(2-benzothiazolyl)thio-2-butyl]-2-chloroadenosine (0.93 g, 51%)(following column chromatography), ¹ H NMR (DMSO-d₆) δ 1.38 (3H, d,--CH₂ CH₃), 1.65-1.86 (2H, m, --CH₂ CH₃), 3.95 (1H, q, H-4'), 4.14 (1H,d, H-3'), 4.48-4.62 (2H, m, H-2' and --CHCH₂ H₃), 5.07 (1H, t, 5'-OH),5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.34, 7.45 (2H,2t, Ar-H), 7.84, 8.0 (2H, 2d, Ar-H). HPLC retention time 21.8 min[gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].

C₂₁ H₂₃ CIN₆ O₄ S₂. requires C, 48.2; H, 4.4; N, 16.1. Found: C, 47.9;H, 4.5; N, 15.7%.

EXAMPLE 16N-[1-(2-Benzothiazolyl)thio-3-methyl-2-butyl]-2-chloroadenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[2-amino-3-methyl-1-butylthio]benzothiazole hydrochloride (1.37 g, 4.2mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.57 g,3.5 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[1-(2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol. This provided the titleN-[1-(2-benzothiazolyl)thio-3-methyl-2-butyl]-2-chloroadenosine (0.69 g,37%) as a foam (mixture of diastereoisomers) (following columnchromatography), ¹ H NMR (DMSO-d₆) δ 0.97-1.05 [6H, m, --CH(CH₃)₂ ],2.0-2.13 [1H, m, --CH(CH₃)₂ ], 3.50-3.70 (3H, m, H-5'_(a) and H-5'_(b)and --CH--), 3.88-3.97 (2H, m, H-4' and --CH--), 5.02, 5.06 (1 H, 2t,5'-OH), 5.21, 5.50 (2H, 2d, 2'- and 3'-OH), 5.32 (1H, dd, H-1'), 7.36,7.46 (2H, 2t, Ar-H). HPLC retention time 23.8 min [gradient elution,20-80% acetonitrile/water (containing 0.1% TFA)].

C₂₂ H₂₅ CIN₆ O₄ S₂, requires C, 49.2; H, 4.7; N, 15.7. Found: C, 49.3;H, 5.0; N, 15.4%.

EXAMPLE 17N-[3-(2-Benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosine

The title compound was prepared according to method A.2-(N-tert-butyloxycarbonyl)amino-1,1,1-trifluoro-3-propanol was preparedby reaction of 2-hydroxymethyl-3,3,3-trifluoropropionic acid (3.16 g, 20mmol) with diphenylphosphoryl azide (5.50 g, 20 mmol)in tert-butanol.The resultant 4-(trifluoromethyl)oxazolidin-2-one was treated withhydrochloric acid to afford 2-amino-3,3,3-trifluoropropanol. This aminewas N-Boc protected under standard conditions (see Example 18) toprovide 2-(N-tert-butyloxycarbonyl)amino-1,1,1-trifluoro-3-propanol(0.65 g), TLC R_(f) 0.37 [SiO₂ ; ethyl acetate/cyclohexane (1:1)].

N-[3-(2-Benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosinewas prepared according to general method A as described in Example 1 byreacting 2-[(R)-2-amino-1,1,1-trifluoro-3-propylthio]benzothiazolehydrochloride [prepared by a Mitsunobu reaction as described in Example1 using the above2-(N-tert-butyloxycarbonyl)amino-1,1,1-trifluoro-3-propanol and2-mercaptobenzothiazole followed by acidic hydrolysis] (0.13 g, 0.47mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-di-chloro-9H-purine (0.21g, 0.45 mmol). Debenzoylation of the purified2',3',5'-tri-O-acetyl-N-[3-(2-benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosinein methanolic ammonia (20 ml) (previously saturated at -10° C.) providedthe titleN-[3-(2-benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosine(0.12 g, 45%) (following column chromatography) [a mixture of (R)- &(S)- diastereoisomers]; ¹ H NMR (DMSO-d₆) δ 3.39-3.49 (1H, m, --CH),3.58, 3.68 (2H, ABX, H-5'_(a) and H-5'_(b)), 3.98 (1H, q, H-4'), 4.11-4.18 (2H, m, H-3' and --CH--), 4.47-4.56 (1H, m, H-2'), 5.08 (1H, m,5'-OH), 5.18-5.28 (1H, m, --CHCH₂ --), 5.27, 5.57 (2H, 2d, 2'- and3'-OH), 5.94 (1H, d, H-1'), 7.08, 7.22, 7.30 (3H, 3 t, Ar-H), 7.71 (1H,d, Ar-H), 8.75 (1H, s, H-8), 8.79 (1H, d, N--H).

EXAMPLE 18trans-N-[2-[(2-Benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine

trans-N-(tert-Butyloxycarbonyl)-2-hydroxycyclopentylamine (see WO93/23418) was prepared as a mixture of enantiomers by reaction ofcyclopentene epoxide (8.0 g, 95.1 mmol) with a 25% aqueous ammoniasolution (35 ml) in a sealed glass vessel at 110° C. for 1.5 h. Thereaction mixture was cooled and evaporated to half its original volumebefore 1N sodium hydroxide solution (95 ml) and THF (100 ml) wereintroduced at 0° C. A solution of di-tert-butyl dicarbonate (21.8 g,99.6 mmol) in THF (50 ml) was added dropwise and the reaction mixturestirred at room temperature for 18 h. The phases were separated and theaqueous phase was washed with ethyl acetate (100 ml). The organic phaseswere combined and washed with saturated brine (100 ml), dried (MgSO₄)and evaporated. The solid residue was recrystallised from a 10:1 mixtureof heptane and ethyl acetate (55 ml) to provide an analytical sample oftrans-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine (4.06 g, 21%),mp 103-105° C.

C₁₀ H₁₉ NO₃ requires C, 59.7; H, 9.5; N, 7.0. Found: C, 59.6; H, 9.8; N,7.0%.

The above trans-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine(24.7 g, 123 mmol) (prepared as described in Example 11) was dissolvedin THF (500 ml) and 4-nitrobenzoic acid (20.51 g, 123 mmol) was added,followed by triphenylphosphine (48.28 g, 184 mmol). A solution ofdiethylazodicarboxylate (32.06 g, 184 mmol) in THF (250 ml) wasintroduced dropwise. The reaction mixture was stirred for 18 h at roomtemperature, evaporated and purified by flash chromatography elutingwith a mixture of cyclohexane and ethyl acetate (4:1) to provide theintermediate 4-nitrobenzoyl ester as a solid (25.5 g), TLC R_(f) 0.52[SiO₂ : cyclohexane/ethyl acetate (1:1)]. This ester was suspended in amixture of a mixture of methanol (180 ml) and 25 % aqueous ammoniasolution (20 ml) and the mixture was stirred at room temperature for 70h before evaporation to a residue. Purification by flash chromatographyeluting with a mixture of cyclohexane and ethyl acetate (4:1 ) providedfractions containing the title compound which crystallised onevaporation to affordcis-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine as a solid (11.0g, 44%), mp 64°-65° C.

trans-N-[2-[(2-Benzothiazolyl)thio]cyclopentyl], 2-chloroadenosine

The above cis-N-(tert-butyloxycarbonyl)-2-hydroxycyclopentylamine wasconverted into trans-2-(2-benzothiazolyl)cyclopentylamine hydrochlorideby the sequence of reactions described in Example 1 (i.e. thioetherformation by the Mitsunobu procedure resulting in inversion at the2-position, followed by acidic hydrolysis of the N-Boc- group).

This trans-2-(2-benzothiazolyl)cyclopentylamine hydrochloride (1.0 g,3.0 mmol) was combined with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-di-chloro-9H-purine (1.34g, 3 mmol) and triethylamine (1.66 ml) and reacted using the proceduredescribed in Example 1. Deacylation of the purified[trans]-2',3',5'-tri-O-acetyl-N-[2-[(2-benzothiazolyl)thio]cyclopentyl]-2-chloroadenosinewas carried out using methanolic ammonia (200 ml) (previously saturatedat -10° C.) which provided the title product as a ca. 1:1 mixture ofdiastereoisomers, HPLC retention time 24.1 and 24.82 min [isocraticelution, 35% acetonitrile/65% water (containing 0.1% TFA)]. A singlediastereoisomer oftrans-N-[2-[(2benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine (0.11g, 7%) was obtained as a foam (following short path columnchromatography), ¹ H NMR (DMSO-d₆) δ 1.65-2.62 (6H, 5m, --CH₂ CH₂ CH₂--), 3.51-3.58 and 3.62-3.69 (2H, ABX, H-5'_(a), and H-5'_(b)), 3.94(1H, br q, H-4'), 4.13 (1H, br q, H-3'), 4.28 (1H, q, --CH--), 4.49 (1H,q, H-2'), 4.68 (1H, m, --CH--), 4.62 (1H, q, H-2'), 5.07 (1H, t, 5'-OH),5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.82 (1H, d, H-1'), 7.35, 7.45 (2H,2t, Ar-H), 7.79, 7.98 (2H, 2d, Ar-H), 8.40 (1H, s, H-8), 8.71 (1H, d,N--H). HPLC retention time 24.82 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₂₂ H₂₃ CIN₆ O₄ S₂. 0.5 EtOH requires C, 49.5; H, 4.7; N, 15.1 . Found:C, 49.1; H, 4.8; N, 14.9%.

EXAMPLE 19 cis-N-[2-[(2-Benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine

trans-N-(tert-Butyloxycarbonyl)-2-hydroxycyclopentylamine (see Example16) was converted into cis-2-(2-benzothiazolyl)cyclopentylaminehydrochloride by the sequence of reactions described in Example 1 (i.e.thioether formation by the Mitsunobu procedure resulting in inversion atthe cyclopentane 2-position, followed by acidic hydrolysis of theBoc-group) (see also WO 93/23418).

The above cis-2-(2-benzothiazolyl)cyclopentylamine hydrochloride (1.5 g,4.6 mmol) was combined with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g,4.5 mmol) and triethylamine (2.49 ml) and reacted by the methoddescribed in Example 1. Deacylation of the purifiedcis-2',3',5'-tri-O-acetyl-N-[2-[(2-benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine using sodium methoxide in methanolprovided the titlecis-N-[2-[(2-benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine (0.89 g,38%) as a foam (following column chromatography) (a ca. 2:1 mixture ofdiastereoisomers), ¹ H NMR (DMSO-d₆) δ 1.62-2.45 (6H, 5m, --CH₂ CH₂ CH₂--), 3.52-3.60 (1H, m, H-5'_(a)), 3.64-3.70 (1H, m, H-5'_(b)), 3.94 (1H,br q, H-4'), 4.11 (1H, br q, H-3'), 4.62 (1H, q, H-2'), 5.75-5.83 (1H,2m, H-1'), 7.26-7.94 (4H, 4m, Ar-H).

EXAMPLE 20N-[(R)-1-(6-Amino-2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting6-amino-2-[(R)-2-aminopropyl-1-propylthio]benzothiazole hydrochloride[prepared by a Mitsunobu reaction as described in Example 1 using2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (13.1 g, 75 mmol) and6-amino-2-mercaptobenzothiazole (13.7 g, 75 mmol) followed by acidichydrolysis]) (2.51 g, 7.2 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.68 g,6.0 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-N-[(R)-1-(6-amino-2-benzothiazolyl)thio-2-propyl]-2-chloroadenosinein methanolic ammonia (200 ml) (previously saturated at -10° C.) toprovide the titleN-[(R)-1-(6-amino2-benzothiazolyl)thio-2-propyl]-2chloroadenosine (1.97g, 63%) as a foam (following column chromatography), ¹ H NMR (DMSO-d₆) δ1.36 (3H, d, --CHCH₃), 3,50-3.71 (4H, m, H-5'_(a) and H-5'_(b) and --CH₂--), 3.95 (1H, d, H-4'), 4.14 (1H, d, H-3'), 4.53 (1H, q, H-2'), 4.63(1H, m, --CH), 5.08 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH),5.83 (1H, d, H-1'), 6.71, 6.99, 7.53 (3H, 3d, Ar-H), 8.41 (1H, s, H-8),8.52 (1H, d, N--H). HPLC retention time 10.29 min [gradient elution,20-80% acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 212-Chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]-6-ethoxybenzothiazole hydrochloride[prepared by a Mitsunobu reaction as described in Example 1 using2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (3.5 g, 20 mmol) and6-ethoxy-2-mercaptobenzothiazole (4.23 g, 20 mmol) followed by acidichydrolysis] (3.8 g, 11.1 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.1 g,2.5 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the titleN[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine(0.22 g, 17%) as a foam (following column chromatography), ¹ H NMR(DMSO-d₆) δ 1.32-1.40 (6H, m, --CH₂ CH₃ and --CHCH₃), 3.44-3.81 (4H, m,H-5'_(a) and H-5'_(b) and --CH₂ --), 3.97 (1H, d, H-4'), 4.08 (2H, q,--CH₂ CH₃), 4.14 (1H, d, H-3'), 4.53 (1H, q, H-2'), 4.68 (1H, m, --CH),5.09 (1H, t, 5'-OH), 5.23, 5.51 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d,H-1'), 7.06, 7.57, 7.74 (3H, 3d, Ar-H), 8.42 (1H, s, H-8), 8.53 (1H, d,N--H). HPLC retention time 22.4 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₂₂ H₂₅ CIN₆ O₅ S₂. 0.5 H₂ O. 0.2 EtOAc requires C, 47.2; H, 4.8; N,14.5. Found: C, 47.3; H, 4.9; N, 14.3%.

EXAMPLE 222-Chloro-N-[(R)-1-(5-chloro-2-benzothiazolyl)thio-2-propyl]adenosine

The title compound was prepared according to general method A asdescribed above in Example 1 by reacting2-[(R)-2-amino-1-propylthio]-5-chlorobenzothiazole hydrochloride[prepared by a Mitsunobu reaction as described in Example 1]with2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (1.75 g, 10 mmol) and5-chloro-2-mercaptobenzothiazole (2.02 g, 10 mmol) followed by acidichydrolysis] (0.5 g, 1.5 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.54 g,1.2 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(5-chloro-2-benzothiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the titleN-[(R)-1-(5-chloro-2-benzothiazolyl)thio-2-propyl]2-chloroadenosine(0.30 g, 46%) as a solid, mp 145 ° C. (following column chromatography),¹ H NMR (DMSO-d₆) δ 1.39 (3H, d, --CHCH₃), 3.45-3.78 (4H, m, H-5'_(a)and H-5'_(b) and --CH₂ --), 3.96 (1H, q, H-4'), 4.14 (1H, t, H-3'), 4.52(1H, t, H-2'), 4.72 (1H, m,-CH), 5.84 (1H, d, H-1'), 7.41 (1H, dd,Ar-H), 7.94 (1H, s, Ar-H), 8.02 (1H, dd, Ar-H), 8.42 (1H, s, H-8), 8.52(1H, d, N--H). HPLC retention time 23.58 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

C₂₀ H₂₀ Cl₂ N₆ O₄ S₂. 1.0 H₂ O requires C, 42.8; H, 3.9; N, 15.0. Found:C, 42.9; H, 3.8; N, 14.8%.

EXAMPLE 23 2-Chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine

The title compound was prepared according to method A as described inExample 1 by reacting 2-[(R)-2-amino-1-propylthio]thiophenehydrochloride [prepared by a Mitsunobu reaction as described in Example1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (7.53 g, 43mmol) and 2-mercaptothiophene (5.00 g, 43 mmol) followed by acidichydrolysis] (0.63 g, 3.0 mmol) with9-(2,3,5-tri-O-acetyl-B-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.12 g,2.5 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the title2-chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine (0.95 g, 82%) as afoam after column chromatography. ¹ H NMR (DMSO-d₆) δ 1.26 (3H, d,--CHCH₃), 2.95-3.18 (2H, ABX, --CH₂ --S--), 3.55 and 3.61 (2H, ABX,H-5'_(a) and H-5'_(b)), 3.95 (1H, q, H-4), 4.14 (1H, t, H-3'), 4.44 (1H,m, --CHCH₃), 4.54 (1H, t, H-2'), 5.84 (1H, d, H-1'), 7.03 (1H, t, Ar-H),7.23, 7.61 (2H, 2d, Ar-H), 8.38 (1H, d,-NH), 8.42 (1H, s, H-2). HPLCretention time 19.5 min [gradient elution, 20-80% acetonitrile/water(containing 0.1% TFA)].

C₁₇ H₂₀ CIN₅ O₄ S₂ requires C, 44.6; H, 4.4; N, 15.3. Found: C, 44.2; H,4.5; N, 15.0%.

EXAMPLE 24 2-Chloro-N-[(R)-1-(4-methyl-1,2,4-triazol-3-yl)thio-2-propyl]adenosine

The title compound was prepared according to method A as described inExample 1 by reacting3-[(R)-2-amino-1-propylthio]-4-methyl-1,2,4-triazole hydrochloride[prepared by a Mitsunobu reaction as described in Example 1 using2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (3.5 g, 20 mmol) and3-mercapto-4-methyl-1,2,4-triazole (2.3 g, 20 mmol) followed by acidichydrolysis] (0.56 g, 2.2 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g,2.2 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(4-methyl-1,2,4-triazol-3-yl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the title2-chloro-N[(R)-1-(4-methyl-1,2,4-triazol-3-yl)thio-2-propyl]adenosine(0.17 g, 17%) as a foam after column chromatography. ¹ H NMR (DMSO-d₆) δ1.24 (3H, d, --CHCH₃), 3.56, 3.67 (2H, ABX, 5'_(a) and H-5'_(b)), 3.95(1H, q, H-4), 4.14 (1H, br q, H-3'), 4.15 -4.42 (2H, m, --CH₂ S--), 4.52(1H, br q, H-2'), 4.80 (1H, m, --CHCH₃), 5.07 (1H, br, 5'-OH), 5.22,5.50 (2H, 2 br, 2'- and 3'-OH), 5.82 (1H, d, H-1'), 8.33 (1H, d,-NH),8.39, 8.41 (2H, 2s, H-2 and Ar-H). HPLC retention time 7.79 min[gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 25 N-[(R)-1-(2-Benzimidazolyl)thio-2-propyl]-2-chloroadenosine

The title compound was prepared according to method A as described inExample 1 by reacting 2-[(R)-2-amino-1-propylthio]benzimidazolehydrochloride [prepared by a Mitsunobu reaction as described in Example1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (1.75 g, 10mmol) and 2-mercaptobenzimidazole (1.5 g, 10 mmol) followed by acidichydrolysis] (0.63 g, 2.20 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.0 g,2.2 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzimidazolyl)thio-2-propyl]-2-chloroadenosinein methanolic ammonia (200 ml) (previously saturated at -10° C.) toprovide the titleN-[(R)-1-(2-benzimidazolyl)thio-2-propyl]-2-chloroadenosine (0.52 g,51%) mp 213°-215° C. after column chromatography and trituration withdichloromethane; ¹ H NMR (DMSO-d₆) δ 1.38 (3H, d, --CHCH₃), 3.95 (1H, q,H-4), 4.12 (1 H, br q, H-3'), 4.42-4.70 (2H, m, --CHCH₃ and H-2'), 5.07(1H, br, 5'-OH), 5.22, 5.50 (2H, 2 br, 2'- and 3'-OH), 5.82 (1H, d,H-1'), 7.04-7.57 (4H, 2m, Ar-H) 8.42 (1H, s, H-2), 8.73 (1H, d, --NH).HPLC retention time 13.7 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 262-Chloro-N-[(R)-1-(4-phenyl-2-thiazolyl)thio-2-propyl]adenosine

The title compound was prepared according to method A as described inExample 1 by reacting 2-[(R)-2-amino-1-propylthio]-4-phenylthiazolehydrochloride [prepared by a Mitsunobu reaction as described in Example1 using 2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (2.72 g, 15.5mmol) and 2-mercapto-4-phenylthiazole (3.0 g, 15.5 mmol) followed byacidic hydrolysis] (1.15 g, 4.0 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.5 g,3.35 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(4-phenyl-2-thiazolyl)thio-2-propyl]adenosineusing sodium methoxide in methanol to provide the title2-chloro-N-[(R)-1-(4-phenyl- 2-thiazolyl)thio-2-propyl]adenosine (0.36g, 20%) as a foam after column chromatography. ¹ H NMR (DMSO-d₆) δ 1.37(3H, d, --CHCH₃), 3.4-3.73 (2H, m, 5'_(a) and H-5'_(b) and --CH₂ --S--),3.94 (1H, q, H-4), 4.13 (1H, q, H-3'), 4.52 (1H, q, H-2'), 4.71 (1H, m,--CHCH₃), 5.06 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83(1H, d, H-1'), 7.33, 7.42 (3H, dt, Ar-H), 7.91 (2H, d, Ar-H), 8.41 (1H,s, H-2), 8.47 (1H, d, --NH). HPLC retention time 18.99 min [gradientelution, 20-80% acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 272-Chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine

The title compound was prepared according to method A as described inExample 1 by reacting3-[(R)-2-amino-1-propylthio]-5-phenyl-1,2,4-triazole hydrochloride[prepared by a Mitsunobu reaction as described in Example 1 using2-[(R)-N-tert-butyloxycarbonyl]amino-1-propanol (2.0 g, 11.4 mmol) and3-mercapto-5-phenyl-1,2,4-triazole (2.0 g, 11 mmol) followed by acidichydrolysis] (0.50 g, 1.8 mmol) with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.75 g,1.7 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosineusing sodium methoxide in methanol to provide the title2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine(0.21 g, 24%) as a foam after column chromatography. ¹ H NMR (DMSO-d₆)51.34 (3H, d, --CHCH₃), 3.37-3.70 (4H, m, --CH₂ --, H-5'_(a) andH-5'_(b)), 3.95 (1H, q, H-4), 4.13 (1H, t, H-3'), 4.53 (1H, t, H-2'),4.59-4.69 (1H, m, --CHCH₃), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'-and 3'-OH), 5.83 (1H, d, H-1'), 7.43-7.54 (3H, m, Ar-H), 7.90, 8.0 (2H,m, Ar-H), 8.40 (1H, s, H-2). 8.42 (1H, d, --NH), HPLC retention time14.5 min [gradient elution, 20-80% acetonitrile/water (containing 0.1%TFA)].

C₂₁ H₂₃ CIN₈ O₄ S. 1.0 H₂ O .0.15 C₇ H₁₆ requires C, 48.0; H, 5.0; N,20,3. Found: C, 48.2; H, 4.8; N, 20.2%.

EXAMPLE 28 N-[(R)-2-(2-Benzothiazolylthio)-1-ethyl]-2-chloroadenosine

2-(2-Benzothiazolylthio)ethylamine dihydrochloride was prepared bystandard synthetic steps with a by Mitsunobu reaction betweenN-(2-hydroxyethyl)phthalimide and 2-mercaptobenzothiazole, followed byreaction with hydrazine hydrate. This amine dihydrochloride (0.52 g,2.11 mmol) was reacted with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.79 g,1.7 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-N-[(R)-2(2-benzothiazolylthio)-1-ethyl]-2-chloroadenosineusing sodium methoxide in methanol to provide the titleN-[(R)-2-(2-benzothiazolylthio)-1-ethyl]-2-chloroadenosine as a foamafter column chromatography, ¹ H NMR (DMSO-d₆) δ 3.54-3.60 and 3.64-3.71(4H, m, H-5'_(a) and H-5'_(b) and --CH₂ --), 3.42, (2H, q, --CH₂ --),3.96 (1H, d, H-4'), 4.15 (1H, q, H-3'), 4.52 (1H, q, H-2'), 5.08 (1H, t,5'-OH), 5.22, 5.51 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 7.38,7.48 (2H, 2t, Ar-H), 7.85, 8.02 (2H, 2d, Ar-H), 8.43 (1H, s, H-8), 8.68(1H, t, N--H). HPLC retention time 18.5 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 29 N-[(R)-1-(2-Benzothiazolyl)amino-2-propyl]-2-chloroadenosine

2-[(R)-N-tertobutyloxycarbonylamino]-1-propylamine was prepared bystandard synthetic steps from(R)-2-(N-tert-butyloxycarbonylamino)-1-propanol by Mitsunobu reactionwith phthalimide followed by reaction with hydrazine hydrate. This amine(0.52 g, 3.0 mmol) and 2-chlorobenzothiazole (0.76 g, 4.5 mmol) weredissolved in dioxan (20 ml) and triethylamine (0.83 ml, 6.0 mmol) wasintroduced. The reaction mixture was heated at 50° C. for 18 h,evaporated and purified by "flash" column chromatography, eluting withheptane/ethyl acetate (10:3) to provide the2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylamino]benzothiazole(0.09 g, 10%) as an oil, TLC R_(f) 0.31 [SiO₂ ; hexane/ethyl acetate(10:3)].

2-[(R)-(2-Amino-1-propyl)amino]benzothiazole trihydrochloride (0.065 g,70%), m.p. 226-226° C., was subsequently obtained by hydrolysis in amixture of 6N hydrochloric acid and ethyl acetate (2 ml), the proceduredescribed in Example 1. This2-[(R)-(2-amino-1-propyl)amino]benzothiazole trihydrochloride (0.06 g,0. 19 mmol) was reacted with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-di-chloro-9H-purine (0.127g, 1.2 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)amino-2-propyl]-2-chloroadenosineusing sodium methoxide in methanol (to remove the 2' and 3'-acetylgroups) followed by ethylamine in ethanol, which provided the titleN-[(R)-1-(2-benzothiazolyl)amino-2-propyl]-2-chloroadenosine (0.027 g,29%) as a foam (following column chromatography), ¹ H NMR (DMSO-d₆) δ1.25 (3H, d, --CHCH₃), 3.52-3.70 (4H, m, H-5'_(a) , H-5'_(b) and --CH₂--), 3.94 (1H, q, H-4'), 4.12 (1H, q, H-3'), 4.52 (1H, q, H-2'), 4.53-4.62 (1H, m, --CHCH₃), 5.07 (1H, t, 5'-OH), 5.22, 5.48 (2H, 2d, 2'- and3'-OH), 5.84 (1H, d, H-1'), 7.01, 7.22 (2H, 2t, Ar-H), 7.43, 7.66 (2H,2d, Ar-H), 8.14 (1H, t, N--H), 8.41 (1H, s, H-8), 8.44 (1H, d, N--H).HPLC retention time 10.7 min [gradient elution, 20-80%acetonitrile/water (containing 0. 1% TFA)].

EXAMPLE 30N-[(R)-1-(2-Benzothiazolylsulphonyl)-2-propyl]-2-chloroadenosine

2-[(R)-2-(N-tert-Butyloxycarbonylamino)-1-propylsulphonyl]benzothiazolewas prepared by oxidation of2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylthio]benzothiazole (seeExample 5) (0.55 g, 1.7 mmol) with "Oxone" on a Montmorillionitesupport. A mixture of the sulphonyl and sulphinyl derivatives wasobtained, and the2-[(R)-2-(N-tert-butyloxycarbonylamino)-1-propylsulphonyl]benzothiazolewas isolated following column chromatography. Deprotection was performedunder standard conditions with hydrogen chloride in ethyl acetate. Theresultant 2-[(R)-2-aminopropyl-1-propylsulphonyl]benzothiazolehydrochloride (0.088 g, 0.4 mmol) was reacted with9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (0.18 g,0.4 mmol), followed by deacylation of the purified2',3',5'-tri-O-acetyl-N-[(R)-1-(2-benzothiazolyl)sulphonyl-2-propyl]-2-chloroadenosineusing sodium methoxide in methanol provided the titleN-[(R)-1-(2-benzothiazolyl)sulphonyl-2-propyl]-2-chloroadenosine as afoam (following column chromatography); ¹ H NMR (DMSO-d₆) δ 1.83 (3H, d,--CHCH₃), 3,55, 3.66 (2H, ABX, H- 5'_(a) and H-5'_(b)), 3.96 (1H, q,H-4'), 4.17 (1H, q, H-3'), 4.59 (1H, q, H-2'), 5.08 (1H, t, 5'-OH),5.24, 5.68 (2H, 2d, 2'- and 3'-OH), 5.95 (1H, d, H-1'), 7.34, 7.47 (2H,2t, Ar-H), 7.84, 8.01 (2H, 2d, Ar-H), 8.14 (1H, t, N--H), 8.71 (1H, s,H-8). HPLC retention time 13.5 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

EXAMPLE 315'-O-Acetyl-2-chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine

Partial deacylation of the purified2',3',5'-tri-O-acetyl-2-chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine(described in Example 19) using sodium methoxide in methanol providedthe title5'-O-acetyl-N-[(R)-1-(6ethoxy2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine(0.070 g, 18%) as a foam (following column chromatography), ¹ H NMR(DMSO-d₆) δ 1.34-1.41 (6H, m, --CH₂ CH₃ and --CHCH₃), 2.03 (3H, s,--COCH₃), 4.60 (1H, q, H-2'), 4.68 (1H, m, -CHCH₃), 5.42, 5.62 (2H, 2d,2'- and 3'-OH), 5.86 (1H, d, H-1'), 7.04 (1H, dd, Ar-H), 7.57, 7.72 (2H,2d, Ar-H), 8.38 (1H, s, H-8), 8.52 (1H, d, N--H). HPLC retention time25.6 min [gradient elution, 20-80% acetonitrile/water (containing 0.1%TFA)].

C₂₄ H₂₇ CIN6₈ O₆ S₂, 0.5 H2O .0.2 C₇ H₁₄ requires C, 48.9; H, 5.0; N,13.5. Found: C, 48.7; H, 4.9; N, 13.4%.

EXAMPLE 325'-O-Acetyl-2-chloro-N-{(R)-1-[5-phenyl,(1,2,4-triazol-3-yl)]thio-2-propyl}-adenosine

Partial deacylation of the purified2',3',5'-Tri-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine(described in Example 27) using sodium methoxide in methanol to providethe title 5'-O-acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3yl)]thio-2-propyl}-adenosine (0.035 g, 8%) as a foam after columnchromatography. ¹ H NMR (DMSO-d₆) δ 1.34 (3H, d, --CHCH₃), 2.02 (3H, s,--COCH3), 4.53-4.68 (2H, q, H-2' and --CHCH₃), 5.40, 5.61 (2H, 2d, 2'-and 3'-OH), 5.86 (1H, d, H-1'), 7.38-8.01 (5H, 3m, Ar-H), 8.37 (1H, s,H-2). HPLC retention time 16.9 min [gradient elution, 20-80%acetonitrile/water (containing 0.1% TFA)].

We claim:
 1. A compound of formula I ##STR9## wherein X is halogen,trifluoromethyl, C₁₋₆ -alkoxy, C₁₋₆ -alkylthio or cyano;R¹ is H,straight or branched C₁₋₆ -alkyl or trifluoromethyl; R⁴ is H or straightor branched C₁₋₆ -alkyl; or R¹ and R⁴ together form a cyclobutyl,cyclopentyl or cyclohexyl ring; Y is O, S, SO₂, N--H or N-alkyl; R⁵ is agroup of formula XI or XII: ##STR10## wherein A is NH, O or S; B is CHor N; C is CH or N; and the group is substituted with R⁸ which is H,phenyl, C₁₋₆ -alkyl, trifluoromethyl, amino, hydroxy, C₁₋₆ -alkoxy,cyano or halogen; R⁶ is hydrogen, benzoyl or C₁₋₆ -alkanoyl and R⁷ ishydrogen, benzoyl or C₁₋₆ -alkanoyl; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1, wherein X is Cl and Yis O, S, SO₂ or N--H.
 3. A compound according to claim 2, wherein R¹ isH, straight or branched C₁₋₆ -alkyl or trifluoromethyl.
 4. A compoundaccording to claim 2, wherein R⁴ is H or straight or branched C₁₋₆-alkyl.
 5. A compound according to claim 2, wherein R⁵ is the group offormula XI.
 6. A compound according to claim 2, wherein R⁵ is the groupof formula XII.
 7. A compound according to claim 2, wherein B is N.
 8. Acompound according to claim 7, wherein A is S.
 9. A compound accordingto claim 1, wherein A is S and X is halogen.
 10. A compound according toclaim 9,wherein Y is S, R⁶ is hydrogen and R⁷ is hydrogen.
 11. Acompound according to claim 1 whichis:2-Chloro-N-[(R)-1-(2-thiazolyl)thio-2-propyl]adenosine;2-Chloro-N-[(R)-1-(4-phenyl-2-thiazolyl)thio-2-propyl]adenosine; or apharmaceutically acceptable salt thereof.
 12. A compound according toclaim 1 whichis:2-Chloro-N-[(R)-1-(1-methyl-2-imidazolyl)thio-2-propyl)adenosine or apharmaceutically acceptable salt thereof.
 13. A compound according toclaim 1 whichis:2-Chloro-N-{(R)-1-[5-methyl-(1,3,4-thiadiazol-2-yl)]thio-2-propyl}adenosineor a pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 1 whichis:N-[(R)-1-(2-Benzoxazolyl)thio-2-propyl]-2-chloroadenosine or apharmaceutically acceptable salt thereof.
 15. A compound according toclaim 1 whichis:N-[(S)-1-(2-Benzothiazolyl)thio-2-propyl]-2-chloroadenosine;N-[(S)-1-(2-Benzothiazolyl)thio-1-propyl]-2-chloroadenosine;N-[(R)-1-(2-Benzothiazolyl)thio-2-butyl]-2-chloroadenosine;N-[(R)-1-(2-Benzothiazolyl)thio-3-methyl-2-butyl]-2-chloroadenosine;N-[3-(2-Benzothiazolyl)thio-1,1,1-trifluoro-2-propyl]-2-chloroadenosine;N-[(R)-1-(6-Amino-2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine;2-Chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine;2-Chloro-N-[(R)-1-(5-chloro-2-benzothiazolyl)thio-2-propyl]adenosine;N-[2-Benzothiazolyl)thio-1-ethyl]-2-chloroadenosine;N-[(R)-1-(2-Benzothiazolyl)amino-2-propyl]-2-chloroadenosine;N-[(R)-1-(2-Benzothiazolyl)sulphonyl-2-propyl]-2-chloroadenosine; '-O-Acetyl-2-chloro-N-[(R)-1-(6-ethoxy-2-benzothiazolyl)thio-2-propyl]adenosine;or a pharmaceutically acceptable salt thereof.
 16. A compound accordingto claim 1 whichis:N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-bromoadenosine;N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-methylthioadenosine;N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-fluoroadenosine; or apharmaceutically acceptable salt thereof.
 17. A compound according toclaim 1 whichis:N-[(R)-1-(2-Benzothiazolyl)thio-2-propyl]-2-chloroadenosine or apharmaceutically acceptable salt thereof.
 18. A compound according toclaim 1 whichis:trans-N-[2-[(2-Benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine;cis-N-[2-[(2-Benzothiazolyl)thio]cyclopentyl]-2-chloroadenosine; or apharmaceutically acceptable salt thereof.
 19. A compound according toclaim 1 which is:2-Chloro-N-[(R)-1-(2-thienyl)thio-2-propyl]adenosine;or a pharmaceutically acceptable salt thereof.
 20. A compound accordingto claim 1 whichis:2-Chloro-N-[(R)-1-(4-methyl-1,2,4-triazol-3-yl)thio-2-propyl]adenosine;2-Chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)thio-2-propyl]}adenosine;5'-O-Acetyl-2-chloro-N-{(R)-1-[5-phenyl-(1,2,4-triazol-3-yl)]thio-2-propyl}adenosine;or a pharmaceutically acceptable salt thereof.
 21. A compound accordingto claim 1 whichis:N-[(R)-1-(2-Benzimidazolyl)thio-2-propyl]-2-chloroadenosine or apharmaceutically acceptable salt thereof.
 22. A compound according toclaim 1 whichis:[1S,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine;[1R,trans]-N-[2-[(2-Benzothiazolyl)thiolcyclobutyl]-2-chloroadenosine;[1S,cis]-N-[2-[( 2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine;[1R,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclobutyl]-2-chloroadenosine;[1S,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine;[1R,trans]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine;[1S,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine;[1R,cis]-N-[2-[(2-Benzothiazolyl)thio]cyclohexyl]-2-chloroadenosine; ora pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising a compound according to claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 24. A pharmaceutical composition according to claim23 in the form of an oral dosage unit containing about 1-200 mg of theactive compound.
 25. A method of treating myocardial ischemia,comprising administering to a person in need of such treatment aneffective amount of a compound of claim
 1. 26. A method of treatingmyocardial ischemia, comprising administering to a person in need ofsuch treatment a pharmaceutical composition according to claim
 23. 27. Amethod of treating cerebral ischemia, comprising administering to aperson in need of such treatment an effective amount of a compound ofclaim
 1. 28. A method of treating cerebral ischemia, comprisingadministering to a person in need of such treatment a pharmaceuticalcomposition according to claim 23.